Connecting the Pieces of the Alzheimer's Puzzle

By

Matt Ridley

Updated April 9, 2011 12:01 a.m. ET

The discovery, announced this week, of several genetic mutations that predispose people toward Alzheimer's disease is intriguing, because the genes are associated with cholesterol metabolism and inflammation. The Alzheimer's jigsaw is a long way from being complete, but the pieces are emerging, and this new evidence fits quite nicely with the other pieces in suggesting a role for inflammation.

ENLARGE

The Alzheimer's jigsaw is a long way from being complete, but the pieces are emerging.
John S. Dykes

Piece 1 is the immediate cause of Alzheimer's disease: the appearance of insoluble "plaques" made of a small protein called amyloid beta (A-beta for short) inside brain cells. These plaques block the traffic of molecules in the cells. Eventually another small protein, called tau, also starts to crystallize in this way to form "tangles." Both symptoms are diagnostic of Alzheimer's, and similar ones characterize other neurological syndromes such as Parkinson's and Creutzfeldt-Jakob's.

Puzzle piece 2 is the APOE gene on chromosome 19, long known as a powerful influence on whether you will get Alzheimer's disease. Having two copies of the 4 version of the gene makes you 20 times more likely than average to get the symptoms before the age of 75. (Having at least one copy of the 2 version makes you less likely than average to get the symptoms.) One of APOE's jobs is to break down plaques, and the 4 version is inefficient at this task.

So right at the heart of the disease is the insolubility of proteins in old age. Proteins in living cells always teeter on the edge of insolubility, because with so many different proteins dissolved in the cell doing different jobs, the total concentration is high and crystallization is a risk. Solubility depends on the correct folding of each protein into a certain shape. With even slight misfolding, a protein may crystallize too easily.

ENLARGE

We can begin to tell a coherent story. Stress and inflammation produce derivatives of cortisol and cholesterol, which trigger misfolding in A-beta proteins.
John S. Dykes

Here is piece 3 of the puzzle. Prof. Chris Dobson of Cambridge University made 17 slight genetic adjustments to the A-beta protein to make it either more or less soluble. He then genetically engineered the mutant proteins into fruit flies and showed that the less soluble the protein, the less coordinated and the shorter-lived were the fruit flies. In effect, by lining up the test-tubes, he could make the dancing flies form a sort of living graph of solubility versus activity.

What makes misfolded proteins appear in elderly brains? Piece 4: Cells have an internal quality-control mechanism that both detects and refolds misfolded proteins. Research published last month by scientists at Brown University revealed that both parts of this mechanism—the detector and the refolder—are working, but overwhelmed, in diseased brains; they can't keep up with the workload of too many misfolded A-beta proteins.

Which brings us to piece 5, this week's announcement of the discovery by Jeffery Kelly and his colleagues at the Scripps Research Institute that a chemical formed when cholesterol reacts with ozone attaches to A-beta and makes the misfolding of it more likely. The ozone comes from inflammation.

Piece 6 is stress—caused by worry, fear, pain, trauma—which shows itself in the production of cortisol, a hormone made from cholesterol. Cortisol, too, is beginning to look like an accomplice in the misfolding of A-beta, according to work at the University of California at Irvine.

So we can begin to tell a coherent story. Stress and inflammation produce derivatives of cortisol and cholesterol, which trigger misfolding in A-beta proteins. This, in turn, overwhelms the cells' quality-assurance mechanism and results in growing numbers of insoluble proteins, which aggregate in plaques and tangles. And this blocks the transport of vital ingredients around brain cells, which causes the cells to die.

Somewhere along this chain, there is a link, we must hope, that can be attacked by medication—to prevent inflammation, discourage ozone reactions, encourage the refolding apparatus, improve protein solubility or boost the plaque-removal mechanism.

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